Lack of Caspase 8 Directs Neuronal Progenitor-like reprogramming and Small Cell Lung Cancer Progression

Mimicry of neuronal features are emerging as malignant regulators of cancer growth and metastasis. Neuroendocrine (NE) cancers and small cell lung cancers (SCLC) in particular have been shown to share expression profiles marking various stages of neuronal differentiation. Yet, how these state changes are caused and malignant consequences thereof have remained unexplored. Here, we devise a novel mouse model of SCLC recapitulating low expression of caspase 8 as seen in humans and uncover that this allows for epigenetic reprogramming towards a more aggressive and metastasising stem-cell like neuronal state. Notably, transcriptional signatures of this neuroendocrine cellular state are enriched in relapsed and metastatic human SCLC. Mechanistically, caspase 8 loss within the pre-tumoral niche promoted immunosuppression and metastasis via induction of immunogenic cell death. Inactivation of the necroptosis executioner Mixed lineage kinase domain-like protein (MLKL) neutralised caspase 8 loss-induced immunosuppression, metastasis and diminished the stem-cell like state providing genetic evidence for a role of necroptosis in promoting these effects. Collectively our data uncover an unexpected role for low expression of caspase 8 in directing neuronal-like reprogramming towards a highly metastatic stem cell-like state in SCLC. Overall design: In order to investigate the role of low Caspase 8 in SCLC development we generated RP mice with conditional deletion of Caspase 8 (RPC mice) and inuced tumor by adeno cre inahlation. Next, from endpoint SCLC tumors of RP and RPC mice we generated cell lines (four of each genotype) and perfomed RNA seq analysis in order to identify the effect of Caspase 8 deletion in RP tumor cells